期刊
AGING CELL
卷 11, 期 1, 页码 139-149出版社
WILEY
DOI: 10.1111/j.1474-9726.2011.00766.x
关键词
insulin-like growth factor-1; Sirtuin-1; oxidative stress; cardiomyocytes
资金
- European Union [LSHM-CT-2005-018630, EUMODIC: LSHG-CT-2006-037188]
- Foundation Leducq (Transatlantic Networks of Excellence Program) [04 CVD 03]
- British Heart Foundation [PG/08/111/26226, PG/10/019]
- EIPOD (EMBL)
- British Heart Foundation [PG/08/111/26226] Funding Source: researchfish
Oxidative stress contributes to the pathogenesis of aging-associated heart failure. Among various signaling pathways mediating oxidative stress, the NAD+-dependent protein deacetylase SirT1 has been implicated in the protection of heart muscle. Expression of a locally acting insulin-like growth factor-1 (IGF-1) propeptide (mIGF-1) helps the heart to recover from infarct and enhances SirT1 expression in cardiomyocytes (CM) in vitro, exerting protection from hypertrophic and oxidative stresses. To study the role of mIGF-1/SirT1 signaling in vivo, we generated cardiac-specific mIGF-1 transgenic mice in which SirT1 was depleted from adult CM in a tamoxifen-inducible and conditional fashion. Analysis of these mice confirmed that mIGF-1-induced SirT1 activity is necessary to protect the heart from paraquat (PQ)-induced oxidative stress and lethality. In cultured CM, mIGF-1 increases SirT1 expression through a c-Jun NH(2)-terminal protein kinase 1 (JNK1)-dependent signaling mechanism. Thus, mIGF-1 protects the heart from oxidative stress via SirT1/JNK1 activity, suggesting new avenues for cardiac therapy during aging and heart failure.
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